ABSTRACT This K24 application is to provide support for protected time for: 1) mentoring/teaching of junior clinical investigators; and 2) patient-oriented research investigating the role of aldosterone in the pathophysiology of diabetic cardiovascular disease. Recent data provide support for the hypothesis that activation of the mineralocorticoid receptor (MR) contributes to diabetic vascular injury, though the mechanisms are uncertain. Consistent with this hypothesis, our pre-clinical studies demonstrate that blockade of MR reduces renal injury in diabetic db/db mice and reduces vascular inflammation and cardiac and renal injury in hypertensive, angiotensin II (ANGII)-infused rodents. Our clinical studies show that short-term treatment with the MR antagonist eplerenone improves coronary circulatory function as compared to treatment with hydrochlorothiazide (HCTZ) in subjects with diabetes receiving angiotensin-converting enzyme (ACE) inhibition therapy. This observation could not be attributed to blood pressure changes suggesting that MR antagonists are not working via a classical renal effect, but via an additional, volume control-independent mechanism. This proposal tests the hypotheses that MR activation contributes to progression of vascular disease in subjects with type 2 diabetes mellitus (T2DM) receiving ACE inhibitor therapy, and consequently, MR antagonists exert beneficial effects by reducing vascular dysfunction and injury, inhibiting ANGII vascular effects, improving coronary circulatory and cardiac function and improving renovascular function. To address these hypotheses we will perform a prospective double-blind study in subjects with T2DM and hypertension receiving chronic ACE inhibitor therapy randomized to one of three treatments: 1) MR antagonist spironolactone; 2) HCTZ plus potassium; and 3) placebo. These studies provide a fertile area for investigation by trainees interested in patient-oriented research and will provide new information about the mechanisms by which MR antagonists reduce diabetic cardiovascular injury, with the goal of introducing new, effective treatments of cardiovascular injury in individuals with diabetes. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE This grant application seeks support for the training and mentoring of a new generation of physicians and investigators interested in performing research in patients with diabetes and heart disease. Diabetes causes injury to blood vessels. This injury leads to many health problems including heart disease, kidney failure and stroke. The goal of this research is to determine whether blocking the actions of a hormone known as aldosterone improves the function of vessels in the hearts and kidneys of patients with type 2 diabetes and whether this leads to improvements in heart and kidney function. Thus, this research may lead to new treatments for patients with diabetes and injury to their hearts and kidneys, and will provide a forum for mentoring trainees in patient-oriented research.